No Charges Filed: The Medical Manslaughter of Jesse Gelsinger

by Robert Helms From Guinea Pig Zero #7

Jesse Gelsinger on June 22, 1999, just after testing at the University of Pennsylvania

Clear the air! Clean the sky! Wash the wind! Take the stone from the stone, take the skin from the arm, take the muscle from the bone, and wash them. Wash the stone, wash the bone, wash the brain, wash the soul, wash them wash them! --T. S. Eliot, Murder in the Cathedral, 1935

Jesse Gelsinger was a bright, optimistic teenager from a working family. His father, Paul Gelsinger, makes his living as a handyman. Paul is divorced from Jesse's mother and re-married, and in the family's new structure, Jesse had five siblings. Jesse suffered from a rare disorder called ornithine transcarbamylase (OTC) deficiency. The lack of this enzyme, traceable to a missing gene, interferes with the liver's ability to metabolize ammonia. The fatal form of this ailment usually takes the lives of newborns and children under age 5, but Jesse's case had been managed by means of medication -- 32 pills a day -- and a special low-protein diet. When the young man kept to the plans set down by his doctors in Arizona, he enjoyed pretty good health and led a relatively normal life.In September 1999, Jesse died in a clinical trial aimed at developing a safe treatment for babies who suffer from the more severe form of the disorder. The research was conducted at the University of Pennsylvania in Philadelphia. His case caused many urgent questions to be raised about how genetic research is conducted in the United States. Let's switch to a factual time-line, gleaned from press reports of the Gelsinger case, after which I will make a few conclusions. -------------------------------Jesse Gelsinger and the Medical Scientists: a Chronology

1981June 18: Jesse Gelsinger is born 1983 Jesse is diagnosed with the non-fatal form of OTC deficiency. 1992 James M. Wilson founds a for-profit, private firm named Genovo, Inc., which will, by 1999, provide $4.7 million annually (of a $22 million budget) to the Institute for Human Gene Therapy at the University of Pennsylvania, which Wilson also directs. Dr. Wilson is a major shareholder of Genovo. 1993April: Mark Batshaw and Wilson begin experiments on OTC deficient mice. Eventually they demonstrate the efficacy of the adenovirus as a vector for the OTC gene, but the results of safety studies on mice, rhesus monkeys, and baboons give mixed results. Three monkeys die from an early, stronger version of the vector, then others suffer severe hepatitis from the same one Jesse would receive. 1994 Batshaw and Wilson seek advice from the University's resident bioethics expert, Arthur Caplan, about how to select human subjects for the next phase of the adenovirus research. Caplan advises against using babies dying from OTC deficiency, in favor of asymptomatic, adult patients like Jesse. The researchers begin scouting for possible volunteers for the clinical trial. 1995Mid-year: The Recombinant DNA Advisory Committee of the National Institutes of Health approves the Batshaw-Wilson protocol, with two dissenting experts stating that it is too risky for asymptomatic volunteers (such as Jesse). Nineteen OTC-deficient adults eventually enroll for a safety study that gradually increases the dosage in each successive group of three, so that the maximum safe dosage level can be determined for humans. The consent forms they sign do not mention the deaths and hepatitis observed in the animal experiments. Jesse is in the last group, and will receive the highest dosage planned for the trial. 1998December: Jesse suffers a severe bout with the disorder because he has strayed from his regimen of medications. He is hospitalized and becomes comatose, but then recovers. 1999May: Jesse graduates from high school.June 18: The Gelsinger family flies to Philadelphia for Jesse's screening at the Hospital of the University of Pennsylvania. They take in the tourist sites. It is Jesse's 18th birthday.June 22: Jesse qualifies for the Batshaw-Wilson study, with a blood-ammonia reading of 47 micromoles per liter, which is below the maximum of 75 specified by the protocol. Normal ammonia is 35. Jesse is thrilled, and he returns home to Arizona.September 9: Jesse flies back to Philadelphia for the adenovirus study. Shortly before leaving, he says a friend: "What's the worst that can happen to me? I die, and it's for the babies."September 12: Jesse reports for duty at the University. His blood-ammonia reading is 91 micromoles. Although this reading far exceeds the limit set by the protocol, the experiment proceeds.September 13, 10:30 a.m.: Jesse's hepatic artery is injected with 30 milliliters of the genetically altered adenovirus and he is given medications that reduce the ammonia level in his blood. After 2 hours, the ammonia reading drops to 60. The surgeon who performs all this work is Steven E. Raper.September 14: After the 20th hour of the experiment, Jesse develops jaundice (turns yellow) because of a certain clotting disorder that was already observed in the dead rhesus monkeys earlier in this research. He sinks into a coma, then into "multiple organ system failure," and is placed on life-support.September 17: Jesse is found to be brain-dead, removed from life support, and pronounced dead. At least nine family members are present.September 28: The University of Pennsylvania announces that Jesse died as the result of a gene-therapy experiment, and the story is reported world-wide.October 11: The US Food and Drug Administration forbids any new subjects from entering all other there were two ongoing trials that are similar to the Batshaw-Wilson study, but those already under treatment are allowed to continue.November 3: The Washington Post reports that researchers and drug manufacturers have failed to inform the National Institutes of Health of 6 deaths that have occurred in gene-therapy experiments since April 1998.November 7: Jesse's ashes are scattered on Mount Wrightson, near his home in Tuscon, by family and friends who carried his remains in his pill bottles. Dr. Raper is present.November 9-10: Public hearings are held at the NIH's headquarters in Bethesda, MD on Jesse's case. Batshaw, Wilson, and Raper begin to admit to discrepancies between the research protocol and their performance, but still defend their conduct. Government officials from the Recombinant DNA Advisory Committee cite the researchers for:

Removing language from the consent forms that described animal deaths and sickness earlier in the research;

Failing to promptly report that two volunteers in the study suffered severe reactions at dosages lower than the one Jesse received (they reported this 2 months later, and proceeded with higher dosages without consulting FDA);

Changing the order of the patients without asking permission (Jesse was second in his set of three, but as the male subject he was supposed to be third).

Proceeding with the experiment when Jesse's ammonia reading exceeded the maximum allowed by the protocol.

Paul Gelsinger speaks at the hearing, urging all parties to draw positive results from his son's death. Through this point in the ordeal, he has stated that he does not hold the researchers responsible for the tragedy.

2000January 21: The FDA shuts down all gene therapy experiments at the University of Pennsylvania after finding "numerous serious deficiencies" in the way Jesse's study was run.January 26: NY Times reports that Paul Gelsinger has hired a lawyer, but also that he wants for Batshaw and Wilson to continue doing gene therapy research (provided they improve their procedures). Also, the Times reports that the Senate will hold a subcommittee hearing on whether there is sufficient oversight for gene therapy.January 30: More tardy news comes from Washington: A Harvard-affiliated hospital in Boston suspended a gene-therapy experiment during the summer of 1999 after three of the first six patients died and a seventh fell seriously ill. Reports of 691 serious adverse events in gene-therapy experiments swamped the NIH as a result of the Gelsinger case. Federal rules demand that adverse event reports be filed "immediately" as problems arise. But 652 of the 691 had never before been seen by the NIH, according to an agency summary requested by Congress. That means less than 6 percent were filed on time. The researchers explained the lateness by their unawareness of the requirement, even though it is stated clearly on the paperwork that gives approval to every experiment they do.February 2: Delores Aderman, another volunteer in the Wilson-Batshaw experiment, steps forward. She tells the Philadelphia Inquirer that in her case, her liver enzymes (which serve as gauges of liver-cell injury) rose to levels high enough that the researchers reported the toxicity to the federal Food and Drug Administration and were obligated to get permission to proceed to the next patient. All the doctors told her was that "everything went good."February 4 - 6: Arthur Caplan and PENN's President write pieces for the Inquirer, defending their institution without specifically defending the conduct of the Wilson-Batshaw trial.February 8: A public panel discussion on genetics and human nature by Wilson and Caplan happens on schedule, but Wilson is replaced at the last minute by a colleague. The facilitator states that Wilson was "unable to make it." Jesse's case was mentioned several times, without discussing the breaches of trust involved. Politicians are ridiculed. Caplan showed that he is an highly skilled public speaker, a born comedian, and an apologist for his home team above all else-----------------------------

Now, let's explore the reasons why this young fellow, in relatively good health, was ever strapped into a table, fitted through the groin with arterial catheters, and infused with an experimental gene-vector, in spite of the blood-ammonia reading that should have disqualified him from the procedure. Before we can do that, we must ask, who are these people at the University of Pennsylvania? Arthur L. Caplan is the director of the university's Center for Bioethics, and has become the most quoted person in his field in recent years. He is peculiar in that he is far more visible and Media-friendly than any of his peers. Some say he's right in popularizing important discussions, while others say he's just another media whore. In either case, Caplan is a team player, and he does not publicly criticize any researcher who practices under the same roof as he does himself. In Guinea Pig Zero #6, I pointed out his odd silence on the subject of the dermatologist Albert Kligman, who used prisoners at Philadelphia's Holmesburg prison as human guinea pigs from the 1950's through the early '70's. In exchange for small cash payments, Kligman tested LSD, dioxin, radioactive isotopes, Agent Orange, and poison ivy on the inmates. He became very rich (he invented Retin-A), and the prisoners became scarred, insane, chronically ill for unknown reasons, and underwent excruciating pain. When prisoner-experiments came under public scrutiny and Kligman was investigated, he destroyed all his original patient records. This is why I do not say that he killed any prisoners. There were questions about dead inmates, but Kligman destroyed the answers. For all that, Art Caplan has no opinion as to whether the surviving inmate guinea pigs should be compensated or otherwise relieved by the university that tortured them. Since the release of Acres of Skin in 1998, a book documenting Kligman's research, most everyone else in the city does. I saw Caplan at a conference on science and religion last spring. The distinguished professor remarked in passing about how those gentlemen outside on the sidewalk (Holmesburg veterans, chanting with picket signs) had reached their conclusions by some logical method as opposed to another. No one would understand what he meant, unless they'd had special training, but he saved face by giving them a nod. But what he said did not in any way reflect upon Kligman's past behavior and the university's refusal to take responsibility for the harm suffered by his living victims. In the case of Jesse Gelsinger, the bioethics poster-boy was the one who made the experiment possible by persuading the researchers and government overseers that asymptomatic adult patients, as opposed to infants with fatal cases, should serve as the human subjects. The reasoning was that the parents would be coerced by the sickness of their babies. Caplan's letter of Feb. 4th fiercely defended why adult OTC deficient persons like Jesse should be put at risk when they were not the intended beneficiaries of the treatment. He ridiculed a reporter who had taken this up as an issue. The letter's effect was to draw the reader's attention away from the more disturbing facts of the case. Caplan's name occurs also back in September, when he argued for an immediate announcement about the nature of Jesse's death. After that, there's been not a word on the glaring conflict of interest on the part of Dr. James M. Wilson, both co-author of the experiment's protocol and one who stood to make many millions if the vector proved marketable. It is obvious that Caplan knows which side his ethical bread is buttered on. When Arthur Caplan, an ethics expert, remains silent on alarming ethical crises, in cases where the players are his own colleagues and when his salary and professional future are controlled by the institution that's directly vested in the matter, he services as the university's spin doctor. To be sure, he did not directly praise them. But, of all people, Caplan is the one whose position should be the clearest and loudest when there is an ethical conflict. We should keep in mind, above all, that he participated in planning the clinical trial that took Gelsinger's life, almost as directly as the researchers themselves. Dr. Mark Batshaw, a pediatrician of great stature, was, according to the New York Times report on Jesse's death, the scientist hardest hit by the tragedy The paper quoted him as saying that he had never, before Jesse, made a patient worse by his care. The paper states that he prayed for the dead boy, and thought hard about the Hippocratic Oath: "I did harm," Batshaw said. Dr. Steve Raper, the driven scientist, has "thrown himself into his work," and committed himself to finding the treatment that the experiment was intended to find, so that this loss of life would not be in vain, according to the Times. As he pronounced Gelsinger dead, he said, "Goodbye, Jesse. We'll figure this out." Later, he pondered whether the vector had reacted badly with Jesse's medications, or whether the reactions in the rhesus monkeys had meant more than he realized. As it happens, I'm wondering about the same things, and experts on the matter from elsewhere are discussing the matter publicly. For example, geneticist Robert Malone of the University of Maryland told the Inquirer that "There was adequate literature to show the adenovirus was a problem - even from [animal studies in] Wilson's own lab. The writing was on the wall for five years." Raper is the surgeon who physically performed the experiment on Jesse Gelsinger, and who agreed to proceed with the infusion even though Jesse's ammonia level was over the allowed maximum on the day the experiment began. Doctors Batshaw and Raper had interpreted "day of enrollment" to mean something different from "day of the treatment" and decided that the lines drawn for Jesse's safety should not interfere with their ambitious experiment. Let's remember that Batshaw wrote the protocol. Batshaw believed that 75 micromoles was the safe limit, and so he wrote in the protocol that the line was drawn at 75. Why would he bend his own rule when Jesse arrived with 91 micromoles, less than three months later? 91 micromoles was not only over the stated limit, but it's nearly double the reading of 47 that Jesse had showed when he enrolled. Why did Raper agree to go ahead with the experiment? Did Raper explain his decision to Jesse? The answer, I believe, lies with Dr. James M. Wilson. This man is not just a physician, but a financial investor as well. When Jesse was strapped in and catheterized in a hospital room in West Philadelphia, Wilson was almost done with an experiment that was expected to make him very rich and world-famous. After his great experiment proved fatal for young Jesse, he aired his feelings to New York Times journalist Sheryl Gay Stolberg, about whether he should have done anything differently: "At this point, I say no, but I'm continuing to re-evaluate constantly." The journalist continues, describing Wilson as "besieged by worry, about the morale of his staff, about whether his financial sponsors would pull out, about whether patients would continue to volunteer, about whether he would lose his bravado - the death knell for scientist on the cutting edge." "'My concern," he [Wilson] confessed, over dinner one night in Philadelphia, "is, I'm going to get timid, that I'll get risk averse.'" Let's remember that the New York Times is not a confrontational paper, nor is it the least bit radical. When its reporter asked Wilson how he felt, she was not trying to set him up, nor would her editors have been likely to print any extremely embarrassing quotes, had she submitted any. We live in an age when major publications are terribly afraid of being sued, and almost never take chances with muck-raking articles on powerful institutions like the University of Pennsylvania. James Wilson was not embarrassed to say that he has a clear business interest in the experiment that cost Gelsinger his life, nor is he shy about telling the world that he's plagued, not by remorse for being too bold with the risks he put his patient into, but rather by the chance that his business life will be harmed by Jesse's death. With the smell of a dead guinea pig following him around, he won't be half the scientific cowboy we've all grown to know and love.

I am led to the conclusion that doctors Wilson, Batshaw, and Raper put Jesse Gelsinger at more risk than they knew to be safe because they stood to personally gain monetary rewards from the teenager's reckless adventure. However, it's clear enough that only Wilson is oblivious to the problem. Finally, who am I to say that Jesse was not mature enough to decide that this experiment was a safe enough bet, for the lives he might help to save for OTC deficient babies? Who am I to contradict Jesse's father, who has refused, till recently, to turn against the researchers at all, who still holds them essentially blameless, and who wishes to keep Jesse's sacrifice in the most positive light possible? Firstly, I am reminded of my own youth when I read descriptions of Jesse's heroic attitude as he went to war against his own disease. Before Jesse was born, I joined the Navy and walked into boot camp to have my head shaved on my 18th birthday, precisely Jesse's age when he first arrived in Philadelphia. Had I been a few years older, I wouldn't have done that. As I matured, I became less easy to persuade. Jesse, by the way, was too young to order a beer in the hotel bar across the street from the hospital where he died. Secondly, I have a special concern that Paul Gelsinger does not have: I personally volunteer my own body for medical experiments. Every time I do this, I sign a consent form, just like Jesse did. Every time I sign, I base my consent on the information written on the form, and usually on nothing else. Doctors Wilson and Batshaw deliberately altered the consent form to touch the reader's eye more softly than the known facts would have. They removed the reports of death and hepatitis in rhesus monkeys, so as not to alarm Jesse and Paul Gelsinger. If they get away with this deceit, then I will have to swallow very hard when I again lower my pen to a consent form. I'll have to look more carefully into the eyes of the doctor, as he or she hands me the little plastic cup with the capsule lying in it: Are his thoughts like my thoughts? Where is his money? Do I see ambition in that steady stare? Does a human heart beat under that lab coat, or is this a lizard, clinging to a financial pipeline with the suction-cup fingers of one hand, and to the flesh of my arm with the other? There are two ways by which this story touches home for me: Jesse was not only a fellow human guinea pig, but the son of a fellow handyman as well. A handyman is a guy who looks for jobs and has them fall in his lap, but only on the merit of his past performance. He is both reliable and trustworthy, or he starves. I know the eye contact between handyman and customer when they say, "Here are the keys to my house." Paul Gelsinger is a handyman who was persuaded by three Ivy League scientists that his boy was safe in their hands. He now sees that he was wrong to trust them and that they were playing from a position of enormous advantage. The media's treatment of Jesse's doctors has been quite mild, and the government's has been cautious, at least until shortly before this writing. Once again the Congress is planning a subcommittee hearing. I am underwhelmed by the shallow courage of our elected leaders. First there was Senator Glenn's bill; it went nowhere. Then came Representative Shays' other initiative that went nowhere too. Here comes another round with Jesse's name all over it, and certain officials at the National Institutes of Health and the Office for Protection from Research Risks are sounding good. However, until I'm proven wrong, I say that this government lacks the raw power and the will to directly force researchers to tell their subjects everything, and to respect the subject's safety as much as they guard their own. There are simply too many dollars and too many Arthur Caplans on the Industry Team. The NIH is now showing us that they care in a bureaucratic way -- but also that they have yet to force researchers even to know what the rules are. There never will be any law that researchers will fear with their own skins, as a regular guy would if he considers peddling drugs to a neighbor's kid. Researchers lie to subjects and grow rich, but they fear no jail sentence, no handcuffs. Bad press and loss of face is the worst it ever gets. I expect to hear some discussion of tightened regulations, and a few changes in the system of oversight for genetic research, but not much else. With Paul Gelsinger's lawsuit, should he bring one and I sure hope he does, money will change hands and all parties will fall silent forever. I hope, also, that Mr. Gelsinger will not allow himself to be seduced again, this time with scholarships named for his son, statues, memorial lecture series, and all that. Paul's statements in the Times worry me that he might do just that: "they should not be put out of business... I don't want to see anybody lose their job..." Jesse Gelsinger died trying to do the world some good, and three researchers walked him toward his death trying to be first to find a very profitable scientific breakthrough. Such is life and death for an honest young man in the medical marketplace.